ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche
Abstract Acute myeloid leukemia (AML) patients present with CD8 exhaustion signatures, and pharmacologic inhibition of checkpoints can have therapeutic benefit. The alarmin IL-33 and its receptor STimulation-2 (ST2) promote activation of tissue-regulatory T cells (Treg cells) and accelerate malignan...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61647-8 |
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| author | Hua Jiang Denggang Fu Santhosh Kumar Pasupuleti Baskar Ramdas Alan Long Abdulraouf M. Ramadan Jinfeng Yang Ramesh Kumar Jessica H. Hartman B. Jacob Kendrick Ed Simpson Hongyu Gao Yunlong Liu Drew Moore Suganya Subramanian Stefano Berto Anilkumar Gopalakrishnapillai Sonali P. Barwe Hongfen Guo Nai-Kong V. Cheung Reuben Kapur Sophie Paczesny |
| author_facet | Hua Jiang Denggang Fu Santhosh Kumar Pasupuleti Baskar Ramdas Alan Long Abdulraouf M. Ramadan Jinfeng Yang Ramesh Kumar Jessica H. Hartman B. Jacob Kendrick Ed Simpson Hongyu Gao Yunlong Liu Drew Moore Suganya Subramanian Stefano Berto Anilkumar Gopalakrishnapillai Sonali P. Barwe Hongfen Guo Nai-Kong V. Cheung Reuben Kapur Sophie Paczesny |
| author_sort | Hua Jiang |
| collection | DOAJ |
| description | Abstract Acute myeloid leukemia (AML) patients present with CD8 exhaustion signatures, and pharmacologic inhibition of checkpoints can have therapeutic benefit. The alarmin IL-33 and its receptor STimulation-2 (ST2) promote activation of tissue-regulatory T cells (Treg cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2+ Treg cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8+ T cells depletion and exhaustion. ST2 deficiency in Treg cells restores CD8+ T cell function, decreasing AML growth via retention of ST2+ Treg cells precursors in lymph nodes. AML-activated ST2+ Treg cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8+ T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed Treg cells. Engineered anti-ST2 antibodies induce ST2+ Treg cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy. |
| format | Article |
| id | doaj-art-7ffe24cff4e2478bab1acbc8627f6926 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7ffe24cff4e2478bab1acbc8627f69262025-08-20T03:05:09ZengNature PortfolioNature Communications2041-17232025-07-0116112610.1038/s41467-025-61647-8ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic nicheHua Jiang0Denggang Fu1Santhosh Kumar Pasupuleti2Baskar Ramdas3Alan Long4Abdulraouf M. Ramadan5Jinfeng Yang6Ramesh Kumar7Jessica H. Hartman8B. Jacob Kendrick9Ed Simpson10Hongyu Gao11Yunlong Liu12Drew Moore13Suganya Subramanian14Stefano Berto15Anilkumar Gopalakrishnapillai16Sonali P. Barwe17Hongfen Guo18Nai-Kong V. Cheung19Reuben Kapur20Sophie Paczesny21Department of Microbiology and Immunology and Department of Pediatrics, Medical University of South CarolinaDepartment of Microbiology and Immunology and Department of Pediatrics, Medical University of South CarolinaDepartment of Pediatrics, Indiana University School of MedicineDepartment of Pediatrics, Indiana University School of MedicineDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDepartment of Pediatrics, Indiana University School of MedicineDepartment of Pediatrics, Indiana University School of MedicineDepartment of Pediatrics, Indiana University School of MedicineDepartment of Biochemistry and Molecular Biology, Medical University of South CarolinaFlow Cytometry & Cell Sorting Shared Resource, Medical University of South CarolinaCenter for Computational Biology & Bioinformatics, Indiana University School of MedicineCenter for Computational Biology & Bioinformatics, Indiana University School of MedicineCenter for Computational Biology & Bioinformatics, Indiana University School of MedicineBioinformatics Shared Resource, Medical University of South CarolinaBioinformatics Shared Resource, Medical University of South CarolinaBioinformatics Shared Resource, Medical University of South CarolinaNemours Children’s Hospital, Lisa Dean Moseley Foundation Institute of Cancer and Blood DisordersNemours Children’s Hospital, Lisa Dean Moseley Foundation Institute of Cancer and Blood DisordersDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDepartment of Pediatrics, Indiana University School of MedicineDepartment of Microbiology and Immunology and Department of Pediatrics, Medical University of South CarolinaAbstract Acute myeloid leukemia (AML) patients present with CD8 exhaustion signatures, and pharmacologic inhibition of checkpoints can have therapeutic benefit. The alarmin IL-33 and its receptor STimulation-2 (ST2) promote activation of tissue-regulatory T cells (Treg cells) and accelerate malignant progression in solid tumors, but their role in leukemia remains unclear. Here, we show that ST2+ Treg cells are enriched in bone marrow (BM) of humans and mice with AML and promote CD8+ T cells depletion and exhaustion. ST2 deficiency in Treg cells restores CD8+ T cell function, decreasing AML growth via retention of ST2+ Treg cells precursors in lymph nodes. AML-activated ST2+ Treg cells lack T-bet, IFN-γ and Bcl-6, and kill intratumoral CD8+ T cells by amplified granzyme B-mediated cytotoxicity compared to non-AML primed Treg cells. Engineered anti-ST2 antibodies induce ST2+ Treg cells apoptosis to extend survival in AML models. Together, our findings suggest that ST2 is a potential checkpoint target for AML immunotherapy.https://doi.org/10.1038/s41467-025-61647-8 |
| spellingShingle | Hua Jiang Denggang Fu Santhosh Kumar Pasupuleti Baskar Ramdas Alan Long Abdulraouf M. Ramadan Jinfeng Yang Ramesh Kumar Jessica H. Hartman B. Jacob Kendrick Ed Simpson Hongyu Gao Yunlong Liu Drew Moore Suganya Subramanian Stefano Berto Anilkumar Gopalakrishnapillai Sonali P. Barwe Hongfen Guo Nai-Kong V. Cheung Reuben Kapur Sophie Paczesny ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche Nature Communications |
| title | ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche |
| title_full | ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche |
| title_fullStr | ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche |
| title_full_unstemmed | ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche |
| title_short | ST2/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche |
| title_sort | st2 il 33 axis blockade inhibits regulatory t cell cytotoxicity towards cd8 t cells in the leukemic niche |
| url | https://doi.org/10.1038/s41467-025-61647-8 |
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